The polyphenols found in green tea extracts are (−)-epicatechin (EC), (−)-epigallocatechin (EGC), (−)-epicatechin-3-gallate (ECG) and (−)-epigallocatechin-3-gallate (EGCG). In particular, (−)-EGCG, the most abundant catechin, was found to be chemopreventive and anticancer agent among the green tea catechins (GTCs) (4. Fujiki, H. J Cancer Res Clin Oncol. 1999, 125, 589-97).
Proteasome is a large protein complex with multicatalytic activities that are responsible for the degradation of not only obsolete and misfolded proteins, but also regulatory proteins involved in cell cycle and apoptosis. In proteasome-dependent proteolysis, ubiquitin is first conjugated to the substrate, followed by degradation of the substrate and recycling of the amino acids and ubiquitin. The ubiquitin/proteasome-dependent degradation pathway plays an essential role in up-regulation of cell proliferation, down-regulation of cell death, and development of drug resistance in human tumor cells. Therefore, proteasome inhibitors show great potential as novel anticancer drugs (Dou, Q. P.; Li, B. Drug Resist Update 1999, 2, 215-23). It has been shown that natural (−)-EGCG and synthetically derived (+)-EGCG are potent inhibitors of the proteasomal chymotrypsin activity, leading to growth arrest and/or apoptosis (Smith, D. M.; Wang, Z.; Kazi, A.; Li, L.; Chan, T. H.; Dou, Q. P. Mol Med 2002, 8: 382-92.). US patent publication no. 20040110790 (Zaveri et al.) describes synthetic analogs of green tea polyphenols as chemotherapeutic and chemopreventive agents, but the synthesis provided only racemic compounds, and do not use natural occurring catechins derived from green tea.
The P13K/Akt signaling is a widely known tumor cell survival pathway (Vanhaesebroeck, B.; Alessi, D. R. Biochein J 2000, 346, 561-76). Blocking this pathway is considered as an important mechanism for inhibiting tumor growth. Phosphorylated Akt (pAkt) is the activated form of Akt. Once Akt is activated, it can mediate cell cycle progression by phosphorylation and consequent inhibition of the cyclindependent kinase inhibitor p27.24 Recently, (−)-EGCG has been found to inhibit the Akt kinase activity via reducing the phosphatidylinositol 3-kinase signals in IVEVITV-Her-2/neu mouse mammary tumor NF639 cells, leading to reduced tumor cell growth (Pianetti, S.; Guo, S.; Kavanagh, K. T.; Sonenshein, G. E. Cancer Res 2002, 62, 652-5).
However, (−)-EGCG has at least one limitation: it gives poor bioavailability. A study by Nakagawa et al. showed that only 0.012% of (−)-EGCG could be absorbed in rats given 56 mg of (−)-EGCG orally (Nakagawa, K.; Miyazawa, T. Anal Biochem. 1997, 248, 41-9). This low absorption was thought to be due to the poor stability of (−)-EGCG in neutral or alkaline solutions. As pH value of the intestine and body fluid is neutral or slightly alkaline, GTCs will be unstable inside the human body, thus leading to reduced bioavailability.